Delving into the Latest Updates on CPL-207-280 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

GPR40

Mechanism

GPR40 agonists(Free fatty acid receptor 1 agonists)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2Diabetic Neuropathies

Inactive Indication-

Originator Organization

Celon Pharma SA

Active Organization

Celon Pharma SA

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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AbstractAimTo assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G‐protein‐coupled receptor 40 agonist developed to treat type 2 diabetes (T2D).MethodsThe phase 1 study in healthy volunteers (White, age 18–55 years, body mass index 18.5–29.9 kg/m2) was performed after single (24 subjects, 5–480 mg) and multiple (32 subjects, 60–480 mg) once‐daily administration of CPL207280. The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C‐peptide, proinsulin, glucagon levels) observed during the 14‐day treatment period.ResultsNo deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax) or area under the plasma concentration–time curve up to 24 h. However, dose‐normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half‐life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed.ConclusionsCPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single‐daily administration and justifies further development of this therapy for patients with T2D.

01 Dec 2021·European Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and development of CPL207280 as new GPR40/FFA1 agonist

Q1 · MEDICINE

Article

Author: Bazydło-Guzenda, Katarzyna ; Dubiel, Krzysztof ; Dawid, Urszula ; Dzida, Radosław ; Smuga, Damian ; Hołowińska, Dagmara ; Gurba-Bryśkiewicz, Lidia ; Stelmach, Filip ; Buda, Paweł ; Gałązka, Kinga ; Wiśniewski, Krzysztof ; Pieczykolan, Jerzy ; Mach, Mateusz ; Matłoka, Mikołaj ; Wieczorek, Maciej ; Wąsińska-Kałwa, Małgorzata

Due to a unique mechanism that limits the possibility of hypoglycemia, the free fatty acid receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues. In this article, we describe the key aspects leading to the discovery of CPL207280 (13), the design of which focused on long-term safety. The introduction of small, nature-inspired acyclic structural fragments resulted in compounds with retained high potency and a satisfactory pharmacokinetic profile. Optimized synthesis and upscaling provided a stable, solid form of CPL207280-51 (45) with the properties required for the toxicology studies and ongoing clinical trials.

01 Oct 2021·Molecular Pharmacology

CPL207280, a Novel G Protein–Coupled Receptor 40/Free Fatty Acid Receptor 1–Specific Agonist, Shows a Favorable Safety Profile and Exerts Antidiabetic Effects in Type 2 Diabetic Animals

Article

Author: Bazydlo-Guzenda, Katarzyna ; Wieczorek, Maciej ; Teska-Kaminska, Malgorzata ; Pieczykolan, Jerzy ; Kaminska, Bozena ; Dzida, Radoslaw ; Matloka, Mikolaj ; Stelmach, Filip ; Smuga, Damian ; Mach, Mateusz ; Dubiel, Krzysztof ; Vialichka, Varvara ; Hucz-Kalitowska, Joanna ; Buda, Pawel

G protein-coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic β-cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca²⁺]_i). Activation of GPR40 in pancreatic β-cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist-TAK-875 (fasiglifam)-was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca²⁺ influx assay with a human GPR40 protein (EC₅₀ = 80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of glucose-stimulated insulin secretion in mouse MIN6 pancreatic β-cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5 times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47) and selectivity of CPL207280 (at 10 μM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment. SIGNIFICANCE STATEMENT: GPR40 is a well-known and promising target for diabetes. This study is the first to show the safety and effects of CPL207280, a novel GPR40/free fatty acid receptor 1 agonist, on glucose homeostasis both in vitro and in vivo in different diabetic animal models. Therefore, we propose the CPL207280 compound as a novel, glucose-lowering agent, overcoming the unmet medical needs of patients with type 2 diabetes.

100 Deals associated with CPL-207-280

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	PL	Celon Pharma SA	21 Jan 2022
Diabetic Neuropathies	Phase 2	-	Celon Pharma SA	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04622111 (Phase 1, EASD2021)	Phase 1	-	32	CPL207280 60 mg	jbythnedlk(eowqakqgpq) = The administration of CPL207280 was generally safe and well-tolerated with no serious AEs. All adverse events were classified as not related to the study product. No increase in the tested hepatic parameters (ALT, AST, ALP, bilirubin, creatinine) was observed. There were no hypoglycaemia episodes during the study. qayozixuca (opxxnoekbj )	Positive	01 Oct 2021
				CPL207280 480 mg
NCT04622111 (CPL207280, Pubmed \| Mol Pharmacol)	Phase 1	-	68	CPL207280	sjfsvcopig(yjikqfnmcw) = gumxhswwnh fnkhcbnlkt (yeifujaiyc ) View more	-	04 Aug 2021
EASD2018	Not Applicable	Diabetes Mellitus Ca 2+	-	CPL207-280CA	azyjjazhrb(wunrzzhdij) = zfgaujrgzg mkhvovqrax (uobscktmkc )	Positive	03 Oct 2018
				Fasiglifam	azyjjazhrb(wunrzzhdij) = xzzyffbbiz mkhvovqrax (uobscktmkc )